In the United States, approximately 12,000 people each year suffer some form of spinal cord injury (SCI), with over 275,000 people chronically paralyzed from SCI. There are two general types of SCI: complete and incomplete lesions. Complete lesions leave the patient with no motor, sensory, or autonomic function below the level of the lesion. Transection of the spinal cord is the most obvious cause of a complete lesion. The level of the injury in the spinal cord determines exactly what function will be lost, as the spinal nerves that exit the cord below this are absolutely unable to transmit signals to or from the brain. Incomplete lesions can take a variety of forms, and depending on the nature of the trauma, a range of motor and sensory abilities may be present.
Non-traumatic pathologies such as stroke and Parkinson's disease are also often characterized by a patient's inability to successfully translate a desire into the appropriate motions of the relevant limbs. Central nervous system pathologies are often responsible for varying levels of paralysis, which cause immense suffering in the affected population.
The capacity for adult mammalian neurons to regenerate and restore functionality following injury is very limited in the central nervous system (CNS) (Fournier et al., 2001, Curr. Opin. Neurobiol. 11:89-94; Davies et al., 1997, Nature 390:680-683; Qiu et al., 2000, Glia. 29:166-174). Major emphasis has been placed on transplantation of fetal neural tissue or cells as a potential strategy to ameliorate functional deficits and to enhance axons to regenerate in the CNS. In addition, transplantation of fetal tissue has resulted in some functional recovery in neurodegenerative diseases, such as Parkinson's and Huntington's disease (Bjorklund et al., 2000, Nat. Neurosci. 3:537-544). However, clinical use of fetal cells is limited by the availability of donor tissue as well as logistic, immunological, and ethical concerns (Hoffer et al., 1991, Trends Neurosci. 14:384-388; Widner et al., 1988, Brain Res. 472:287-324). Accordingly, there has been enormous attention on finding an alternative source of neurons that are suitable for transplantation and repair. In particular, extensive effort has been placed on neural stem cells as a source of multipotent graft tissue. However, neural stem cells primarily differentiate into glia when transplanted into normeurogenic regions of adult brain or spinal cord (Cao et al., 2001, Exp. Neurol. 167:48-58; Chow et al., 2000, Brain Res. 874:87-106; Fricker et al., 1999, J. Neurosci. 19:5990-6005; Gage et al., 1995, Proc. Natl. Acad. Sci. USA 92:11879-11883; Herrera et al., 1999, Ann. Neurol. 46:867-877; Shihabuddin et al., 2000, J. Neurosci. 20:8727-8735).
Methods for transplantation of neural tissue into the area of an SCI, in order to reduce the deficits associated with the injury and to promote functional recovery, are currently under development. In animal studies, embryonic tissue transplants into the areas of a lesioned spinal cord have been shown to survive and to reinnervate certain regions of the spinal cord (Bjorklund et al., 1986, Neurosci. 18:685-698; Buchanan et al., 1986, Brain Res. 381:225-236; Moorman et al., 1990, Brain Res. 508:194-198; Ribotta et al., 1996, Brain Res. 707:245-255). Such studies have shown that the time of transplant after injury the type of cell transplanted affects the success of the attempted transplant. These transplant studies have focused on reinstating nerve fiber connections using ex vivo donor material or attempting to grow long nerve fibers by attractant molecules. However, neither approach to transplantation has achieved success in growing nerve fibers over a distance of more than a few millimeters.
Other methods attempted as a way to bridge or fill spinal cord injury lesions that include transplanting peripheral nerves, transplanting progenitor cells, transplanting stem cells, or transplanting dissociated cells from nervous tissue (McDonald, 1999, Sci. Amer. 281:64-73; Zompa et al., 1997, J. Neurotrauma 14:479-506). Some of these attempts have resulted in improved functional outcome in animal models of spinal cord injury. However, improved function has not been attributed directly to the reinstatement of spinal cord signals through the transplant. Rather, it has been proposed that the primary benefit of the transplanted tissue in these models is through physical and biochemical support for the host tissue surrounding the lesion (Stichel et al., 1998, Prog. Neurobiol. 56:119-148; Anderson et al., 1995, Brain Pathol. 5:451-457). While the results of these studies have been promising, the goal of re-establishing an axonal connection through a spinal cord lesion has yet to be realized.
Another neural injury is amputation of a digit or limb. Historically, such injuries have been treated by providing a prosthesis. Despite remarkable improvements in the engineering of such prostheses, however, they remain relative cumbersome with limited function. Current prosthetic devices do not replace sensory systems and cannot adapt movements based on sensory feedback as a natural limb functions. In recent years, the concept of neurally-controlled prostheses has become the focus of much research. The strategy is to use regions of the undamaged nervous system to provide command signals to drive prosthetic functions. The most vigorously-pursued approach attempts to harness external recordings obtained from the motor cortex. These non-invasive techniques obtain the user's intent from scalp-derived sensorimotor rhythms, typically those of the mu or beta frequency bands. Studies in rats, non-human primates, and quadriplegic patients have shown that upon sufficient training, the user can learn to move a cursor in two-dimensional space by manipulating these frequencies (Wolpaw et al., 2004, Proc. Natl. Aca. Sci. 101: 17849-17854). While the risk of surgery is avoided in this approach, a sophisticated system requiring several degrees of freedom has not yet been realized.
More invasive techniques have also been developed. These techniques chronically implant micro-electrodes into the primary motor cortex or spinal cord to local record neuronal activity. Neuronal population decoding algorithms are used to decipher the recorded signals in real-time (Kennedy et al., 2004, IEEE Trans. Neural Syst. Rehabil. Eng. 12:339-344). This method, however, involves complex computations, and significant clinical risks arise from the chronic implantation of electrodes. Moreover, findings from functional magnetic resonance imaging studies indicate that there is extensive overlap of the cortical representations of different limb regions, adding additional difficulty to implant positioning and signal decoding (Rao et al., 1995, Neurology 45:919-924).
There remains, therefore, a need in the art for a composition and method of treatment for nerve lesions, such as spinal cord injuries. The invention addresses and meets these needs.